VCV000003758.10 - ClinVar

NM_000375.3(UROS):c.244G>T (p.Val82Phe)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(4)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000375.3(UROS):c.244G>T (p.Val82Phe)

Variation ID: 3758 Accession: VCV000003758.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q26.2 10: 125815034 (GRCh38) [ NCBI UCSC ] 10: 127503603 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 1, 2013	Jan 6, 2024	Jun 22, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000375.3:c.244G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000366.1:p.Val82Phe	missense
NM_001324036.2:c.244G>T	NP_001310965.1:p.Val82Phe	missense
NM_001324037.2:c.244G>T	NP_001310966.1:p.Val82Phe	missense
NM_001324038.2:c.244G>T	NP_001310967.1:p.Val82Phe	missense
NM_001324039.2:c.244G>T	NP_001310968.1:p.Val82Phe	missense
NR_136676.2:n.500G>T		non-coding transcript variant
NR_136677.2:n.500G>T		non-coding transcript variant
NC_000010.11:g.125815034C>A
NC_000010.10:g.127503603C>A
NG_011557.2:g.13235G>T
LRG_1081:g.13235G>T
LRG_1081t1:c.244G>T	LRG_1081p1:p.Val82Phe

... more HGVS ... less HGVS

Protein change

V82F

Other names

p.Val82Phe

Canonical SPDI

NC_000010.11:125815033:C:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00020 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Links

ClinGen: CA340120 OMIM: 606938.0009 dbSNP: rs121908016 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
UROS		-	-	GRCh38 GRCh37	131	199

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Cutaneous porphyria	Uncertain significance (3)	criteria provided, single submitter	Apr 28, 2017	RCV000003956.13
not provided	Uncertain significance (1)	criteria provided, single submitter	Jun 22, 2022	RCV003480019.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Jun 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV004225341.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (4) PubMed: 19099412‚ 22816431‚ 7860775‚ 8829650 Other databases https://www.ncbi.nlm.nih.gov/boo… https://www.ncbi.nlm.nih.gov/books/NBK154652/ Comment: PP3, PM2, PM3_supporting, PS3_supporting Number of individuals with the variant: 1
Uncertain significance (Apr 28, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	Cutaneous porphyria Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000361369.3 First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019	Publications: PubMed (4) PubMed: 19099412‚ 8829650‚ 7860775‚ 22816431 Comment: The UROS c.244G>T (p.Val82Phe) missense variant has been reported in two studies in which it was found in two individuals with congenital erythropoietic porphyria including … (more) The UROS c.244G>T (p.Val82Phe) missense variant has been reported in two studies in which it was found in two individuals with congenital erythropoietic porphyria including in one patient in a compound heterozygous state and in a second patient in a heterozygous state in whom a second variant was not found (Xu et al. 1995; Katugampola et al. 2012). Control data are not available for this variant which is reported at a frequency of 0.00003 in the European (non-Finnish) population of the Exome Aggregation Consortium. This frequency is based on two alleles only in a region of good sequence coverage so the variant is presumed rare. In a functional study by Xu et al. (1995) the p.Val82Phe variant enzyme was expressed in E. coli and demonstrated to have 35.8% residual activity and less thermostability compared to wild type. However, in a similar study by Fortian et al. (2009), the variant was shown to have 93.8% of the specific activity of wild type with no decrease in stability. RNA analysis showed that the p.Val82Phe variant produced two RNA species, one of normal size and one shorter product which was the result of a deletion of exon four. The shorter product accounted for 53.8% of the total RNA produced (Xu et al. 1995). The Val82 residue is not conserved between human and mouse (Xu et al. 1996). Based on the evidence, the p.Val82Phe variant is considered to be a variant of unknown significance, but suspicious for pathogenicity for congenital erythropoietic porphyria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
Pathogenic (Feb 01, 1995)	no assertion criteria provided Method: literature only	PORPHYRIA, CONGENITAL ERYTHROPOIETIC Affected status: not provided Allele origin: germline	OMIM Accession: SCV000024121.3 First in ClinVar: Apr 04, 2013 Last updated: Jun 02, 2019	Publications: PubMed (1) PubMed: 7860775 Comment on evidence: In a patient with congenital erythropoietic porphyria (CEP; 263700), Xu et al. (1995) found a val82-to-phe (V82F) missense mutation in the UROS gene. The mutation … (more) In a patient with congenital erythropoietic porphyria (CEP; 263700), Xu et al. (1995) found a val82-to-phe (V82F) missense mutation in the UROS gene. The mutation occurred adjacent to the 5-prime donor site of intron 4 and resulted in approximately 54% aberrantly spliced transcripts with exon 4 deleted. Thus, this novel exonic single-base substitution caused 2 lesions: an amino acid substitution and an aberrantly spliced transcript. The mutation causing V82F is a G-to-T transversion of the last nucleotide of exon 4. (less)
not provided (-)	no classification provided Method: literature only	Cutaneous porphyria Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000086781.3 First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2022	Publications: BookShelf: NBK154652 BookShelf: NBK154652

Comment:

The UROS c.244G>T (p.Val82Phe) missense variant has been reported in two studies in which it was found in two individuals with congenital erythropoietic porphyria including in one patient in a compound heterozygous state and in a second patient in a heterozygous state in whom a second variant was not found (Xu et al. 1995; Katugampola et al. 2012). Control data are not available for this variant which is reported at a frequency of 0.00003 in the European (non-Finnish) population of the Exome Aggregation Consortium. This frequency is based on two alleles only in a region of good sequence coverage so the variant is presumed rare. In a functional study by Xu et al. (1995) the p.Val82Phe variant enzyme was expressed in E. coli and demonstrated to have 35.8% residual activity and less thermostability compared to wild type. However, in a similar study by Fortian et al. (2009), the variant was shown to have 93.8% of the specific activity of wild type with no decrease in stability. RNA analysis showed that the p.Val82Phe variant produced two RNA species, one of normal size and one shorter product which was the result of a deletion of exon four. The shorter product accounted for 53.8% of the total RNA produced (Xu et al. 1995). The Val82 residue is not conserved between human and mouse (Xu et al. 1996). Based on the evidence, the p.Val82Phe variant is considered to be a variant of unknown significance, but suspicious for pathogenicity for congenital erythropoietic porphyria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Congenital Erythropoietic Porphyria.	Adam MP	-	2021	PMID: 24027798
Congenital erythropoietic porphyria: a single-observer clinical study of 29 cases.	Katugampola RP	The British journal of dermatology	2012	PMID: 22816431
Uroporphyrinogen III synthase mutations related to congenital erythropoietic porphyria identify a key helix for protein stability.	Fortian A	Biochemistry	2009	PMID: 19099412
Molecular basis of congenital erythropoietic porphyria: mutations in the human uroporphyrinogen III synthase gene.	Xu W	Human mutation	1996	PMID: 8829650
Congenital erythropoietic porphyria: identification and expression of 10 mutations in the uroporphyrinogen III synthase gene.	Xu W	The Journal of clinical investigation	1995	PMID: 7860775
https://www.ncbi.nlm.nih.gov/books/NBK154652/	-	-	-	-

Text-mined citations for rs121908016 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jan 06, 2024

ClinVar Genomic variation as it relates to human health

NM_000375.3(UROS):c.244G>T (p.Val82Phe)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121908016 ...